Multiple Myeloma Frontline Treatment Options

When you're diagnosed with multiple myeloma (MM), the first step is frontline, or first-line, treatment. First-line treatment for MM is the first step in managing the disease and improving your quality of life. This initial therapy aims to reduce the number of myeloma cells, relieve symptoms, and improve your overall health. This page will guide you through the different options and help you understand what to expect.

Treatment Plan for Multiple Myeloma 

To determine the best treatment plan for multiple myeloma, your doctor will order several tests, including blood and urine testing, radiologic imaging, and tissue (bone marrow) biopsy. The results of these tests may indicate a precursor condition known as monoclonal gammopathy of undetermined significance (MGUS), or they may indicate the indolent condition of smoldering multiple myeloma (SMM). If you have active myeloma, your doctor will look for specific signs called myeloma-defining events (MDEs) to determine if treatment is needed right away.

How Is Multiple Myeloma Treated?

Multiple myeloma treatment typically involves combinations of medications to get the deepest and most durable response. When needed, medication combinations will be adjusted or changed for continued management. Each new combination is called a line of therapy (LOT). The first LOT for active myeloma is called initial, frontline, or induction treatment. 

When Should You Begin Treatment for Your Multiple Myeloma?

For most patients, treatment will begin after the diagnosis of myeloma is confirmed with a MDE and a bone marrow test. It is important to get treatment started to prevent further medical complications such as infections and kidney or bone damage.  However, there is usually time to discuss the options for frontline treatment,, which may include participating in a clinical trial.

Sometimes, emergency situations may require immediate medical attention. Kidney failure, high blood calcium, active infection, or vertebral fracture that presses on the nerves or spinal cord are examples of emergencies that require immediate intervention. Treatment is directed at the immediate medical issue to preserve renal function, reduce blood calcium, treat infection, or reduce pressure on the spinal cord. Supportive care measures are used in parallel with myeloma treatment to get the disease and symptoms under control.

Useful Resources for Starting Multiple Myeloma Treatment

Starting treatment for multiple myeloma is overwhelming and challenging. Here are some resources to help you remain prepared and confident in the steps ahead:

• Patient Handbook
• Possible Complications Related to Myeloma
• Understanding Your Test Results
• Understanding Clinical Trials in Myeloma 

Why Should You Consult With a Myeloma Expert?

Myeloma is a complex diagnosis with rapidly changing treatment options. A myeloma expert can provide valuable guidance, answer your questions, help you access clinical trials, and make you aware of the latest treatment advances. These specialists can work with your local hematologist to review your plan of care and provide additional recommendations.

Frontline Treatment Options for Multiple Myeloma

This section will guide you through the different multiple myeloma treatment options, helping you make informed decisions with your healthcare team. 

The Use of Four Drugs for Frontline Treatment 

Recent research has shown that a four-drug combination is the optimal treatment for multiple myeloma for most patients. This involves four different drugs:

• A proteasome inhibitor Velcade® (bortezomib) or Kyprolis® (carfilzomib)
• An immunomodulatory agent Revlimid® (lenalidomide)
• A CD38 monoclonal antibody, either Darzalex (dartumumab) or Sarclisa® (Isatuximab)
• The steroid dexamethasone

The primary results of the PERSEUS phase III clinical trial of Darzalex (daratumumab), Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone, or DVRd, in ASCT-eligible patients with NDMM demonstrated that this combination with subcutaneous (SQ) injection of Darzalex Faspro, significantly improved PFS and increased depth of response (DpR) with consistent and clinically meaningful PFS benefit across clinically relevant subgroups when compared to Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone — or VRd — alone.  

The safety profile was consistent with the known safety profiles for Darzalex Faspro and VRd. These data support the use of DVRd followed by maintenance therapy with Darzalex and Revlimid (D-R) as a new standard of care for ASCT-eligible patients with NDMM when compared to VRd alone followed by maintenance with Revlimid.

For Transplant-Eligible Patients 

For younger and fit individuals, frontline therapy is a three-step process that comprises one line of therapy (LOT):

• Induction: Initial treatment to reduce the myeloma burden.
• Autologous Stem Cell Transplant (ASCT): A procedure to replace damaged bone marrow with healthy stem cells.
• Maintenance: Long-term treatment to keep the myeloma in remission

As of July 30, 2024, the United States Food and Drug Administration (U.S. FDA) approved Darzalex (daratumumab or dara) in combination with Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone (Dara-VRd or D-VRd). This approval was based on results from the PERSEUS trial (NCT03710603) and marks D-VRd as the SOC induction therapy for newly diagnosed multiple myeloma patients who are eligible for autologous stem cell transplant.  

Results from the PERSEUS trial show statistically significant benefit in progression-free survival (PFS) and depth of response, both complete response (CR) and minimal residual disease (MRD)-negative status (MRDneg), when dara is added to VRd. Furthermore, Dara-VRd demonstrated PFS of 48 months in 84.3% of trial participants, and complete response or better in 87.9% of participants.  

Minimal residual disease negativity at 10^-5 was seen in 75.2% of trial participants, and at 10^-6 in 65.1% of them. 

Source: Sonneveld P, Dimopoulos MA, Boccadoro M, et al. …PERSEUS Trial Investigators. “Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.” N Engl J Med. 2024 Jan 25;390(4):301-313. 

Standard Induction Therapy — Dara-VRd for Transplant-Eligible Patients

The PERSEUS study confirms the clinical benefits of adding daratumumab to standard VRd therapy. It shows significant improvements in depth of response and long-term disease control, supporting its use in combination regimens for newly diagnosed multiple myeloma patients. 

Daratumumab in combination with VRd is considered the preferred regimen by the National Comprehensive Cancer Network (NCCN) guidelines for primary treatment of myeloma for those who are transplant candidates. 

These drugs are administered as follows: 

• Darzalex® (daratumumab) is given by subcutaneous injection.  
• Velcade (bortezomib) is given by subcutaneous injection.
• Revlimid (lenalidomide) is a pill taken by mouth.  
• Dexamethasone is a steroid taken as a pill by mouth, or it can be given intravenously (IV). 

Additional Induction Therapy Options for Transplant-Eligible Patients

KRd

Kyprolis® (carfilzomib) combined with Velcade, (bortezomib), Revlimid (lenalidomide) and dexamethasone — known as D-KRd — may be used instead of DVRd in patients with high-risk features such as cytogenetic abnormalities in their plasma cells and/or myeloma occurring in soft tissue areas (extramedullary—or outside the bone).  

For patients who have, or are at high risk for peripheral neuropathy, Kyprolis (carfilzomib) may be used instead of Velcade (bortezomib).  

Alternative combinations for frontline therapy for people considered eligible for ASCT include the following:

• Darzalex (daratumumab), Velcade (bortezomib), Cytoxan® (cyclophosphamide), and dexamethasone (DVCd or Dara-CyBorD). Cytoxan is an alkylating agent, a form of chemotherapy for myeloma cancer, that can be taken as a pill by mouth. This combination may be considered if lenalidomide is not available or not preferred initially.  
• Before undergoing ASCT, a person will receive 4-6 cycles of induction therapy to gain control over myeloma cells and to show that the myeloma is responsive to therapy. 

The Stem Cell Transplant Process

The use of autologous stem cell transplant (ASCT) in the upfront setting is part of a multi-step treatment plan and is considered SOC. Alkeran® (melphalan) is intensive chemotherapy. It is given intravenously (through the vein) to eliminate even more of the myeloma after induction therapy. There are additional steps to this process involving eligibility determination, stem cell collection, high-dose chemotherapy followed by stem cell infusion, engraftment, and recovery. Learn more about autologous stem cell transplant here.

Maintenance Therapy

Following recovery from ASCT, approximately 2-3 months, use of maintenance therapy to maintain control over myeloma is recommended. Medications used for induction are often used for maintenance with changes in dose and schedule. Typically, this involves Revlimid alone, or in combination with Darzalex, Velcade, or Kyprolis.

Current standard of care (SOC) does not put a time limit or duration of use for maintenance therapy; however, discontinuation may be considered after 2 years due to recent evidence that standard-risk patients may not benefit from longer maintenance. Length of therapy may also be influenced by bone marrow minimal residual disease (MRD) results. This discussion is important to have with your myeloma specialist.

Resources for Four-Drug Combination for Transplant-Eligible Patients

Stay informed about the four-drug combination for transplant-eligible patients with the following resources:

• Understanding DARZALEX and DARZALEX FASPRO
• Understanding the VRd Regimen for Newly Diagnosed Myeloma
• Understanding Stem Cell Transplant in Myeloma
• Understanding KYPROLIS® (carfilzomib) for Injection
• Tip Card: Alkylating Agents
• Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. (Sonneveld, et al., NEJM, 2024;390(4):301-313.) 

For Transplant-Ineligible Patients 

ASCT is a rigorous treatment process — not all people will be eligible or able to undergo this process due to frailty or age. Some may choose to delay or decline ASCT based on personal circumstances and preferences.  

Isa-VRd for induction

In September 2024, the U.S. Food and Drug Administration (FDA) approved the use of Isa-VRd for patients with newly diagnosed multiple myeloma (NDMM) who are not eligible (TNE) for autologous stem cell transplant (ASCT). This FDA approval of the Isa-VRd regimen was based on the results of the IMROZ phase III clinical trial, which demonstrated longer PFS in ASCT-ineligible patients with NDMM who received Isa-VRd, when compared to patients who received VRd alone.

Also, Sarclisa (isatuximab) in combination with VRd is included in the National Comprehensive Cancer Network (NCCN) guidelines for primary treatment of multiple myeloma for transplant and non-transplant candidates.  

Learn more about the Isa-VRd combination with the following IMF publication:

Understanding the Isa-VRd Regimen in Newly Diagnosed Myeloma

Extended approval of DVRd for transplant-ineligible patients

In 2026, the FDA expanded its approval of DVRd to include patients with NDMM who were ineligible for ASCT or who declined ASCT as frontline therapy. The expanded approval is based on data from the CEPHEUS clinical trial of 395 patients, 197 in the DVRd arm of the study and 198 in the VRd arm (without Darzalex Faspro).

The CEPHEUS study demonstrated significant benefit as measured by MRD-negativity and PFS. MRD-negativity was 52.3% in the DVRd arm vs. 34.8% in the VRd arm. At a follow-up of 54 months, approximately 68% of patients in the DVRd arm remained progression-free vs. approximately 48% in the VRd arm. DVRd demonstrated a 43% lower risk of progression or death vs. VRd.  

Median PFS was not reached in the DVRd arm of the study, indicating superior, long-lasting, durable responses compared to the VRd arm.

The CEPHEUS study confirmed that for patients who are not proceeding to transplant as frontline therapy, DVRd is a new standard of care (SOC).

Additional combination options for transplant-ineligible patients include:   

• DRd, the MAIA regimen: Darzalex® (daratumumab), Revlimid, and dexamethasone  
• VRd Lite, which means the patient will take a VRd regimen with lighter doses of each drug to improve tolerance
• Revlimid and dexamethasone (Rd)  
• Velcade and dexamethasone (Vd) 

Resources on Four-Drug Combinations for Transplant-Ineligible Patients

Here are some valuable resources for transplant-ineligible patients:

• Tip Card: Sarclisa®
• Understanding DARZALEX and DARZALEX FASPRO 
• Understanding the VRd Regimen for Newly Diagnosed Myeloma
• Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma (Facon, et al. NEJM, 2024)
• Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial (Leleu, et al. Nat Med, 2024) 

What Are the Expectations of Frontline Treatment? 

Most patients will experience an excellent response to induction therapy that occurs within the first 2-3 months of treatment. This response is tracked by measuring the myeloma protein levels (free light chains, M-spike, or M-protein) each month. The myeloma has responded if there has been at least a fifty-percent reduction in myeloma protein levels. This is considered a partial response (PR).  

When response continues to 90%, it is known as a very good partial response, or VGPR. If the response shows a 100% reduction in M-protein— such that the M-protein or free lite chains are no longer detectable by traditional methods (SPEP or IFE tests). Then, it is known as complete response or CR (once confirmed with a bone marrow test). Some patients may even achieve MRD-negative status with frontline therapy.  

The expectation of frontline therapy is that response will last, on average, 4-5 years, especially for patients with standard-risk myeloma. For people with high-risk myeloma, this time may be shorter.  

Improvement in Myeloma Symptoms 

Typically, myeloma symptoms improve with response to treatment. For example, CRAB features (Calcium levels, Renal/Kidney function, Anemia, and Bone disease) correct during the first months of treatment, leading to improvement in symptoms. It may be helpful for you to keep a symptom diary to track changes (improvement or worsening) to inform your healthcare team.  

Your healthcare team will repeat blood tests to monitor calcium, creatinine (kidney function), and hemoglobin levels (anemia), as well as monitor response to treatment. Your doctor may also recommend additional imaging studies such as X-rays, MRIs, or CT scans.  

If significant bone damage has occurred, associated pain and other issues may take longer to resolve. Use of radiation therapy, interventional procedures (i.e. vertebroplasty, kyphoplasty, surgery) and pain medication may be needed to manage acute and long-term pain. Bone strengthening medications are used to quickly reduce high calcium levels and reduce the risk of future bone loss and fracture.  

Resources for Managing Myeloma Symptoms and Complications

Below are some resources to help you better understand your symptoms and complications:

• Understanding Your Test Results
• Understanding Fatigue
• Understanding Treatment of Myeloma Bone Disease
• Understanding Treatment of Myeloma-Induced Vertebral Compression Fractures 

What Are Side Effects of Myeloma Treatments?

Typically, D-VRd, Isa-VRD, or alternate combinations are very well tolerated. Close monitoring for any signs or symptoms of infection is of greatest importance, especially in the first few weeks of therapy. During this time, the immune system is compromised because of both myeloma and the treatment. As the treatment begins to destroy the myeloma cells, the immune system becomes more effective. Yet the treatment has a continued immunosuppressive effect. Changes in appetite (increase and decrease), bowel function (constipation and diarrhea), and nerve damage (neuropathy) are possible and can increase over time. As mentioned, maintain a symptom diary and report side effects to your healthcare team.   

Gain a Better Understanding of Myeloma Drugs

Explore the FDA-approved myeloma medications:

• FDA-Approved Drugs for Myeloma page 
• Tip Card: Myeloma and the Immune System 

Myeloma and Treatment Decision-Making 

A diagnosis of multiple myeloma and starting treatment is overwhelming for you and your loved ones. Understanding your treatment options, how they may affect your quality of life, and what matters most to you are key to participating in shared decision-making with your doctor and healthcare team. Together, you will consider the treatment options, including benefits and side effects.     

Be sure to discuss expectations for quality of life, the impact on your career if you are still working, and the impact of treatment on other life activities. The cost of care may also be a consideration for you.  

You, as part of your healthcare team, will need to come to a treatment decision that best manages the myeloma while aligning with your values and preferences.  

Improve Your Doctors' Visits With These Tools 

Here are some tips and tools for your next doctor's visit:

• Tip Card: Myeloma Treatment Discussion Tool
• Tip Card: Ask Your Doctor These Important Questions
• Comprehensive Glossary 

Need More Information? Chat to Myelo!

Have questions about myeloma? Get instant answers with Myelo®, our 24/7 generative AI chatbot. Myelo can provide personalized information, explain complex topics, and guide you to relevant resources.